This U19 application for a hepatitis C Cooperative Research Center (HCV CRC) focuses on the mechanisms employed by HCV to evade or suppress the host immune response. Three highly inter-related projects described below would characterize multiple components of innate and adaptive immunity that influence whether spontaneous resolution or viral persistence occurs. The specific aims of this proposal fulfill several of the stated aims of this RFA, including but not limited to: elucidate the mechanisms and key steps by which HCV deregulates and evades the host immune response at the time of initial infection and during chronic infection (e.g., the role of HCV proteins in blunting the innate immune response, including dendritic cell maturation); examine the role of immune responses associated with more benign outcome of chronic HCV following multiple exposures to virus (e.g., in intravenous drug users), as compared to aggressive and severe outcomes; elucidate the role of viral factors in the establishment and rate of progression of chronic infection; construct prototype vaccine candidates (or other novel immunotherapeutic strategies) and evaluate these in appropriate in vitro and in vivo model systems. Each of the investigators have ongoing collaborations and are committed to the central and difficult problem of immune evasion in HCV infection. The resulting synergy will allow investigators in each laboratory to use tools and approaches that would not be readily available without this multi-center application. Based on preliminary data, the overall goal of this HCV CRC will be to determine how the immune system can successfully protect against and eradicate HCV infection and HCV-related malignancies. More specifically, we hypothesize that: 1) the strength of natural killer and dendritic cell activity early after acute infection correlates with the relative likelihood of spontaneously eradicating virus; 2) the differential activation and repression of the innate cellular signal transduction pathways by HCV proteins affects the outcome of acute infection; 3) the suppressive ability of regulatory CD4+ T cells (perhaps mediated by HCV core binding to gC1R) inhibits the development of protective antiviral T cell immunity.